[1,3]DIAZINO[5,4-d]PYRIMIDINES AS HER2 INHIBITORS

ABSTRACT

The present invention relates to new [1,3]diazino[5,4-d]pyrimidines and derivatives of Formula (I)wherein the groups R1, R2, R3 and R4 have the meanings given in the claims and specification, their use as inhibitors of HER2 and its mutants, pharmaceutical compositions which contain such compounds and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.

FIELD OF THE INVENTION

The present invention relates to new [1,3]diazino[5,4-d]pyrimidines andderivatives of Formula (I)

wherein the groups R¹, R², R³ and R⁴ have the meanings given in theclaims and specification, their use as inhibitors of HER2 and itsmutants, pharmaceutical compositions which contain such compounds andtheir use as medicaments, especially as agents for treatment and/orprevention of oncological diseases.

BACKGROUND OF THE INVENTION

The family of ERBB transmembrane receptor tyrosine kinases (RTKs)consists of the four members EGFR (ERBB1), HER2 (Neu, ERBB2), HER3(ERBB3) and HER4 (ERBB4), which fulfill essential functions duringdevelopment (Citri et al., Nat. Rev. Mol. Cell Biol., 2006, 7(7),505-516; Hynes et al., Curr. Opin. Cell Biol., 2009, 21(2), 177-184;Wang, Z., Methods Mol. Biol., 2017, 1652, 3-35). ERBB signaling isinitiated upon binding of the extracellular domains of EGFR, HER3 orHER4 to their respective ligands and subsequent homo- orheterodimerization of ERBB family members. HER2, for which no ligand hasbeen identified, is the preferred dimerization partner for the otherERBB members. Once an active ligand-receptor complex has been formed,the intracellular tyrosine kinase domains of EGFR, HER2, HER3 or HER4are activated by auto- or transphosphorylation and subsequently elicit asignal transduction cascade most notably engaging the mitogen-activatedprotein (MAP) kinase and/or the phosphoinositide 3-kinase (PI3K)pathways (Citri et al., Nat. Rev. Mol. Cell. Biol., 2006, 7(7), 505-516;Hynes et al., Curr. Opin. Cell Biol., 2009, 21(2), 177-184; Wang, Z.,Methods Mol. Biol., 2017, 1652, 3-35).

Aberrant ERBB signaling is implicated in several pathophysiologicalconditions including cancer or neurological diseases. In cancer, ERBBsignaling is hyper-activated through mutations that render the RTKconstitutively active by promoting dimerization or shifting theequilibrium towards the active conformer of the kinase and/or throughamplification and consequent over-expression of the RTK. Both oncogenicmechanisms increase the net output of ERBB signaling and thereby promotecell survival, cell growth and proliferation (Arteaga et al., CancerCell, 2014, 25(3), 282-303).

Aberrant HER2 signaling is observed in a wide variety of humanmalignancies. Oncogenic mutations are described for the extracellular,(juxta-) membrane and intracellular regions of the protein. Collectivelythese mutations render HER2 constitutively active, fueling cancerinitiation, tumor maintenance and growth (Connell et al., ESMO Open,2017, 2(5), e000279). Similarly, HER2 overexpression increases HER2signaling and underlies neoplastic transformation and tumor maintenancein a variety of indications including breast, gastric or lung cancer.

Consequently, interference with HER2 oncogenic signaling results ininhibition of tumor growth. Targeted therapies include HER2 directedantibodies (including trastuzumab and pertuzumab), HER2 directedantibody-drug conjugates (trastuzumab-DM1 (T-DM1, ado-trastuzumabemtansine)) and small molecules inhibiting the HER2 kinase domain(afatinib, neratinib, lapatinib).

Altogether, tumors driven by HER2 oncogenic mutations or HER2 wild typeover-expression (for example due to gene amplification) might benefitfrom a HER2 specific tyrosine kinase inhibitor (TKI). Collectively, HER2alterations affect up to 6-7% of all human cancers and an EGFR wild typesparing TKI (tyrosine kinase inhibitor) could emerge as an effectivetherapeutic option.

Even though there are HER2 wild type inhibitors that are selective overEGFR wild type, such as tucatinib, these inhibitors do not have efficacyon HER2 carrying exon 20 mutations. Other selective wild type HER2inhibitors have been disclosed in prior art documents WO 2003/049740, WO2007/059257, WO 2005/044302.

HER2 exon 20 mutations constitute a subset of HER2 gain-of-functionmutations that result in enhanced kinase activity (Wang et al. CancerCell, 2006, 10(1), 25-38). This enhanced HER2 kinase activity feeds intodownstream signaling cascades that stimulate neoplastic transformationthrough promoting growth, proliferation and survival of the mutantcells.

Studies in genetically engineered mouse models have demonstrated thatthe most prevalent HER2 exon 20 mutation in NSCLC, the duplication ofthe 4 amino acids YVMA (p.A775_G776insYVMA), is required and sufficientto drive oncogenic growth (Perera et al., Proc. Natl. Acad. Sci. USA,2009, 106(2), 474-479). Withdrawal of HER2-YVMA expression is associatedwith tumor shrinkage, suggesting that this oncogenic variant of HER2 isrequired for tumor maintenance (Perera et al. 2009). In addition, thisstudy demonstrated that in a mouse model, the pan-ERBB blocker Afatinibis efficacious in vivo and can interfere with oncogenic signaling ofHER2-YVMA (Perera et al. 2009).

Oncogenic mutations in HER2 in NSCLC predominantly affect the tyrosinekinase domain of HER2 and cluster in exon 20 of the ERBB2 gene (Stephenset al., Nature, 2004, 431(7008), 525-526). 2-4% of lung cancer patientsare estimated to carry activating mutations in HER2 exon 20. Clinicallyapproved ERBB targeting tyrosine kinase inhibitors are not efficaciousin these patients, as they are limited by EGFR wild type-mediated doselimiting toxicity. Afatinib and other pan-ERBB blockers have shownlimited efficacy in HER2 exon 20 mutated NSCLC patients, mainly due tolimitations in reaching an efficacious dose. In particular, EGFR wildtype mediated toxicity limits efficacious dosing.

Allitinib, ibrutinib, neratinib, poziotinib and pyrotinib are knownpan-ERBB inhibitors of mutant HER2 exon 20. Further inhibitors of mutantHER2 exon 20 have been disclosed in prior art documents WO 2015/175632,WO 2015/195228, WO 2016/183278 and WO 2019/046775.

There is a high unmet medical need for compounds that selectively targetHER2 exon 20 mutant proteins while sparing EGFR wild type to overcomethe disadvantages of EGFR wild type mediated dose limiting toxicity.

It has been found that the compounds of the present invention bind tothe tyrosine kinase domain of wild type and mutant HER2 exon 20 in anorthosteric and covalent manner while sparing EGFR wild type and act asselective inhibitors of wild type HER2 and mutant HER2 carryingmutations in exon 20.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide new inhibitors of mutantHER2 exon 20 that are selective over EGFR wild type. The compounds ofthe invention act as selective inhibitors of HER2 exon 20 and show animproved wild type EGFR sparing efficacy profile in addition to highselectivity over EGFR wild type compared to prior art compounds.

Furthermore, some compounds of the present invention show an improvedpharmacokinetic and pharmacological profile, such as good metabolicstability.

The compounds of the invention are useful for the prevention and/ortreatment of a disease and/or condition characterised by excessive orabnormal cell proliferation, especially in the treatment and/orprevention of cancer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new [1,3]diazino[5,4-d]pyrimidines andderivatives of Formula (I)

-   -   wherein    -   R¹ is selected from the group consisting of hydrogen, —CH₃,        —CCH, —OCH₃ and halogen;    -   R² is hydrogen or halogen;    -   R³ is selected from the group consisting of formula (i.1),        (i.2), (i.3) and (i.4);

-   -   R⁴ is selected from the group consisting of R^(4.a) and R^(4.b)

-   -   wherein    -   Q denotes 4-6 membered heterocyclyl containing 1 N-atom, wherein        one carbon atom of the ring is optionally substituted by methyl;    -   Z denotes 4-6 membered heterocyclyl containing 1 N-atom, wherein        one carbon atom of the ring is optionally substituted by methyl;        R⁵ is H or CH₃;    -   and at least one of R¹ and R² is not hydrogen.

Preferred Embodiments

In another embodiment of the present invention R¹ is selected from thegroup consisting of —CH₃, —CCH, —OCH₃ and halogen.

In another embodiment of the present invention R¹ is selected from thegroup consisting of —CH₃, —CCH, —OCH₃, chlorine and fluorine.

In another embodiment of the present invention R¹ is —CH₃.

In another embodiment of the present invention R¹ is —CCH.

In another embodiment of the present invention R¹ is —OCH₃.

In another embodiment of the present invention R¹ is chlorine.

In another embodiment of the present invention R¹ is fluorine.

In another embodiment of the present invention R¹ is hydrogen.

In another embodiment of the present invention R² is selected from thegroup consisting of hydrogen fluorine and chlorine.

In another embodiment of the present invention R² is hydrogen.

In another embodiment of the present invention R² is halogen.

In another embodiment of the present invention R² is fluorine orchlorine.

In another embodiment of the present invention R² is fluorine.

In another embodiment of the present invention R² is chlorine.

In another embodiment of the present invention R³ is selected from thegroup consisting of formula (i.1), (i.2), (i.3) and (i.4).

In another embodiment of the present invention R³ is a group consistingof formula (i.1) or (i.3).

In another embodiment of the present invention R³ is a group consistingof formula (i.2) or (i.4).

In another embodiment of the present invention R³ is a group consistingof formula (i.1) or (i.2).

In another embodiment of the present invention R³ is a group consistingof formula (i.1) or (i.4).

In another embodiment of the present invention R³ is a group consistingof formula (i.2) or (i.3).

In another embodiment of the present invention R³ is a group consistingof formula (i.3) or (i.4).

In another embodiment of the present invention R³ is a group of formula(i.1).

In another embodiment of the present invention R³ is a group of formula(i.2).

In another embodiment of the present invention R³ is a group of formula(i.3).

In another embodiment of the present invention R³ is a group of formula(i.4).

In another embodiment of the present invention R⁴ is R^(4.a), whereinR^(4.a) is

In another embodiment of the present invention R^(4.a) is R^(4.a.1)wherein R^(4.a.1) is

In another embodiment of the present invention R⁴ is R^(4.b). whereinR^(4.b) is

In another embodiment of the present invention R^(4.b) is R^(4.b.1)wherein R^(4-b-1) is

In another embodiment of the present invention R⁵ is H.

In another embodiment of the present invention R⁵ is CH₃.

In another embodiment of the present invention R⁶ is H.

In another embodiment of the present invention R⁶ is CH₃.

In another embodiment of the present invention m is 1.

In another embodiment of the present invention m is 2.

In another embodiment of the present invention n is 1

In another embodiment of the present invention n is 2.

In another embodiment of the present invention p is 1.

In another embodiment of the present invention p is 2.

In another embodiment of the present invention q is 1.

In another embodiment of the present invention q is 2.

In another embodiment of the present invention Q denotes 4-6 memberedsaturated heterocyclyl containing 1 N-atom, wherein one carbon atom ofthe ring is optionally substituted by methyl.

In another embodiment of the present invention Q denotes 4-6 memberedpartially unsaturated heterocyclyl containing 1 N-atom, wherein onecarbon atom of the ring is optionally substituted by methyl.

In another embodiment of the present invention Q denotes azetidinyl.

In another embodiment of the present invention Q denotes pyrrolidinyl.

In another embodiment of the present invention Q denotes piperidinyl.

In another embodiment of the present invention Q denotes azetidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Q denotes pyrrolidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Q denotes piperidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Z denotes 4-6 memberedsaturated heterocyclyl containing 1 N-atom, wherein one carbon atom ofthe ring is optionally substituted by methyl.

In another embodiment of the present invention Z denotes 4-6 memberedpartially unsaturated heterocyclyl containing 1 N-atom, wherein onecarbon atom of the ring is optionally substituted by methyl.

In another embodiment of the present invention Z denotes azetidinyl.

In another embodiment of the present invention Z denotes pyrrolidinyl.

In another embodiment of the present invention Z denotes piperidinyl.

In another embodiment of the present invention Z denotes azetidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Z denotes pyrrolidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Z denotes piperidinyl,wherein one carbon atom of the ring is substituted by methyl.

In another embodiment of the present invention Q and Z denote 4-6membered saturated heterocyclyl containing 1 N-atom, wherein one carbonatom of the ring is optionally substituted by methyl.

In another embodiment of the present invention Q and Z denote 4-6membered partially unsaturated heterocyclyl containing 1 N-atom, whereinone carbon atom of the ring is optionally substituted by methyl.

Any and each of the definitions of R¹, R², R³, R⁴, R^(4.a), R^(4.a.1),R^(4.b), R^(4.b.1), R⁵, R⁶, m, n, p, q, Q and Z may be combined witheach other.

A preferred embodiment of the current invention are the above compoundsof Formula (I), selected from the group consisting of examples I-01 toI-19.

Example Structure I-01

I-02

I-03

I-04

I-05

I-06

I-07

I-08

I-09

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

-   -   or a pharmaceutically acceptable salt thereof.

A further preferred embodiment of the current invention are the abovecompounds of Formula (I), selected from the group consisting of examplesI-01 to I-19.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the above compounds of Formula (I),selected from the group consisting of examples I-01 to I-19.

A further preferred embodiment of the current invention are the abovecompounds of Formula (I), selected from the group consisting of examplesI-01 to I-13.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the above compounds of Formula (I),selected from the group consisting of examples I-01 to I-13.

A further preferred embodiment of the current invention are the abovecompounds of Formula (I), selected from the group consisting of examplesI-14 to I-19.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the above compounds of Formula (I),selected from the group consisting of examples I-14 to I-19.

A further preferred embodiment of the current invention is the compoundof example I-01.

A further preferred embodiment of the current invention is the compoundof example I-02.

A further preferred embodiment of the current invention is the compoundof example I-03.

A further preferred embodiment of the current invention is the compoundof example I-04.

A further preferred embodiment of the current invention is the compoundof example I-05.

A further preferred embodiment of the current invention is the compoundof example I-06.

A further preferred embodiment of the current invention is the compoundof example I-07.

A further preferred embodiment of the current invention is the compoundof example I-08.

A further preferred embodiment of the current invention is the compoundof example I-09.

A further preferred embodiment of the current invention is the compoundof example I-10.

A further preferred embodiment of the current invention is the compoundof example I-11.

A further preferred embodiment of the current invention is the compoundof example I-12.

A further preferred embodiment of the current invention is the compoundof example I-13.

A further preferred embodiment of the current invention is the compoundof example I-14.

A further preferred embodiment of the current invention is the compoundof example I-15.

A further preferred embodiment of the current invention is the compoundof example I-16.

A further preferred embodiment of the current invention is the compoundof example I-17.

A further preferred embodiment of the current invention is the compoundof example I-18.

A further preferred embodiment of the current invention is the compoundof example I-19.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-01.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-02.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-03.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-04.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-05.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-06.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-07.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-08.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-09.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-10.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-11.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-12.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-13.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-14.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-15.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-16.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-17.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-18.

A further preferred embodiment of the current invention arepharmaceutically acceptable salts of the compound of example I-19.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound of Formula (I) or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients.

Another embodiment of the present invention is a compound of Formula (I)or a pharmaceutically acceptable salt thereof for use as a medicament.

Another embodiment of the present invention is the use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for treating apatient suffering from cancer including brain cancer, breast cancer,biliary cancer, bladder cancer, cervical cancer, colorectal cancer,endometrial cancer, skin cancer, esophagus tumor, head and neck tumor,gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer,lung cancer or prostate cancer.

Another embodiment of the present invention is the use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for treating apatient suffering from breast cancer, bladder cancer, colorectal cancer,gastrointestinal cancer, esophageal cancer or lung cancer.

Another embodiment of the present invention is the use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for treating apatient suffering from cancers/tumors/carcinomas of the lung: e.g.non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindlecell carcinoma, adenocarcinoma, large cell carcinoma, clear cellcarcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cellcancer, intermediate cell cancer, combined oat cell cancer).

Another embodiment of the present invention is the use of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for treating apatient suffering from NSCLC.

Another embodiment of the present invention is a pharmaceuticalcomposition comprising additionally to a compound of Formula (I), apharmaceutically active compound selected from the group consisting of acytostatic and a cytotoxic active substance.

The present invention further relates to hydrates, solvates, polymorphs,metabolites and prodrugs of compounds of Formula (I) thereof.

In another embodiment the invention relates to a pharmaceuticallyacceptable salt of a compound of Formula (I).

In another aspect, the invention relates to a method of inhibiting wildtype and/or mutant HER2 in a cell, comprising contacting the cell with acompound of Formula (I). In another embodiment, the invention relates toa method of inhibiting HER2 carrying exon 20 mutations in a cell,preferably comprising contacting the cell with a compound of Formula(I).

In another aspect, the invention relates to a method of inhibitingphosphorylation of wild type and/or mutant HER2 in a cell, comprisingcontacting the cell with a compound of Formula (I). In anotherembodiment, the invention relates to a method of inhibitingphosphorylation of HER2 exon 20 mutant in a cell, comprising contactingthe cell with a compound of Formula (I).

In another aspect, the invention relates to the use of a compound ofFormula (I)—or a pharmaceutically acceptable salt thereof—for thetreatment and/or prevention of a disease and/or condition, wherein theinhibition of wild type and/or mutant HER2 is of therapeutic benefit. Inanother embodiment, the invention relates to the use of a compound ofFormula (I)—or a pharmaceutically acceptable salt thereof—for thetreatment and/or prevention of a disease and/or condition, wherein theinhibition of HER2 exon 20 mutant protein is of therapeutic benefit.

In another aspect, the invention relates to a compound of Formula (I)—ora pharmaceutically acceptable salt thereof—for use in a method forinhibiting wild type and/or mutant HER2, in a human subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of compound of Formula (I)—or a pharmaceuticallyacceptable salt thereof. In another embodiment, the invention relates toa compound of Formula (I)—or a pharmaceutically acceptable saltthereof—for use in a method for inhibiting HER2 exon 20 mutant, in ahuman subject in need thereof, comprising administering to the subject atherapeutically effective amount of compound of Formula (I)—or apharmaceutically acceptable salt thereof.

In another aspect, the invention relates a compound of Formula (I)—or apharmaceutically acceptable salt thereof—for use as a medicament.

In another aspect, the invention relates to a compound of Formula(I),—or a pharmaceutically acceptable salt thereof—for the treatmentand/or prevention of cancer. In another embodiment, the inventionrelates to a compound of Formula (I)—or a pharmaceutically acceptablesalt thereof—for the treatment and/or prevention of cancer, wherein thecancer is with HER2 overexpression and/or HER2 amplification. In anotherembodiment, the invention relates to a compound of Formula (I)—or apharmaceutically acceptable salt thereof—for the treatment and/orprevention of cancer, wherein the cancer is HER2 exon 20 mutant cancer.In another embodiment, the invention relates to a compound of Formula(I)—or a pharmaceutically acceptable salt thereof—for the treatmentand/or prevention of cancer, wherein the HER2 overexpressed, HER2amplified and/or HER2 exon 20 mutant cancer is selected from braincancer, breast cancer, biliary cancer, bladder cancer, cervical cancer,colorectal cancer, endometrial cancer, skin cancer, esophagus tumor,head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidneycancer, liver cancer, lung cancer and prostate cancer.

In another aspect, the invention relates to a method of treating and/orpreventing above mentioned diseases and conditions comprisingadministering a therapeutically effective amount of a compound ofFormula (I)—or a pharmaceutically acceptable salt thereof—to a human.

In another aspect, the present invention relates to a compound ofFormula (I)—or a pharmaceutically acceptable salt thereof—for use in thetreatment and/or prevention of above mentioned diseases and conditions.

In another aspect the present invention relates to the use of a compoundof Formula (I)—or a pharmaceutically acceptable salt thereof—for thepreparation of a medicament for the treatment and/or prevention of abovementioned diseases and conditions.

Furthermore, the following cancers, tumors and other proliferativediseases may be treated with compounds of the invention, without beingrestricted thereto: Cancers/tumors/carcinomas of the head and neck: e.g.tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses,nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolartrigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx(including base of tongue, tonsil, tonsillar pilar, soft palate,tonsillar fossa, pharyngeal wall), middle ear, larynx (includingsupraglottis, glottis, subglottis, vocal cords), hypopharynx, salivaryglands (including minor salivary glands);

-   -   cancers/tumors/carcinomas of the lung: e.g. non-small cell lung        cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma,        adenocarcinoma, large cell carcinoma, clear cell carcinoma,        bronchioalveolar), small cell lung cancer (SCLC) (oat cell        cancer, intermediate cell cancer, combined oat cell cancer);    -   neoplasms of the mediastinum: e.g. neurogenic tumors (including        neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma,        ganglioneuroblastoma, ganglioneuroma, neuroblastoma,        pheochromocytoma, paraganglioma), germ cell tumors (including        seminoma, teratoma, non-seminoma), thymic tumors (including        thymoma, thymolipoma, thymic carcinoma, thymic carcinoid),        mesenchymal tumors (including fibroma, fibrosarcoma, lipoma,        liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma,        rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma,        hemangioendothelioma, hemangiopericytoma, lymphangioma,        lymphangiopericytoma, lymphangiomyoma);    -   cancers/tumors/carcinomas of the gastrointestinal (GI) tract:        e.g. tumors/carcinomas/cancers of the esophagus, stomach        (gastric cancer), pancreas, liver and biliary tree (including        hepatocellular carcinoma (HCC), e.g. childhood HCC,        fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell        HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC;        hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma;        hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma,        leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin        tumor), gall bladder, extrahepatic bile ducts, small intestine        (including duodenum, jejunum, ileum), large intestine (including        cecum, colon, rectum, anus; colorectal cancer, gastrointestinal        stroma tumor (GIST)), genitourinary system (including kidney,        e.g. renal pelvis, renal cell carcinoma (RCC), nephroblastoma        (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary        bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g.        distal, bulbomembranous, prostatic; prostate (androgen        dependent, androgen independent, castration resistant, hormone        independent, hormone refractory), penis);    -   cancers/tumors/carcinomas of the testis: e.g. seminomas,        non-seminomas; Gynecologic cancers/tumors/carcinomas: e.g.        tumors/carcinomas/cancers of the ovary, fallopian tube,        peritoneum, cervix, vulva, vagina, uterine body (including        endometrium, fundus);    -   cancers/tumors/carcinomas of the breast: e.g. mammary carcinoma        (infiltrating ductal, colloid, lobular invasive, tubular,        adenocystic, papillary, medullary, mucinous), hormone receptor        positive breast cancer (estrogen receptor positive breast        cancer, progesterone receptor positive breast cancer), HER2        positive breast cancer, triple negative breast cancer, Paget's        disease of the breast;    -   cancers/tumors/carcinomas of the endocrine system: e.g.        tumors/carcinomas/cancers of the endocrine glands, thyroid gland        (thyroid carcinomas/tumors; papillary, follicular, anaplastic,        medullary), parathyroid gland (parathyroid carcinoma/tumor),        adrenal cortex (adrenal cortical carcinoma/tumors), pituitary        gland (including prolactinoma, craniopharyngioma), thymus,        adrenal glands, pineal gland, carotid body, islet cell tumors,        paraganglion, pancreatic endocrine tumors (PET;        nonfluorineunctional PET, PPoma, gastrinoma, insulinoma, VIPoma,        glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid        tumors;    -   sarcomas of the soft tissues: e.g. fibrosarcoma, fibrous        histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma,        angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor,        hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon        sheath, solitary fibrous tumor of pleura and peritoneum, diffuse        mesothelioma, malignant peripheral nerve sheath tumor (MPNST),        granular cell tumor, clear cell sarcoma, melanocytic schwannoma,        plexosarcoma, neuroblastoma, ganglioneuroblastoma,        neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma,        extraskeletal chondrosarcoma, extraskeletal osteosarcoma,        mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma,        extrarenal rhabdoid tumor, desmoplastic small cell tumor;        sarcomas of the bone: e.g. myeloma, reticulum cell sarcoma,        chondrosarcoma (including central, peripheral, clear cell,        mesenchymal chondrosarcoma), osteosarcoma (including parosteal,        periosteal, high-grade surface, small cell, radiation-induced        osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant        cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma,        chordoma, small round cell sarcoma, hemangioendothelioma,        hemangiopericytoma, osteochondroma, osteoid osteoma,        osteoblastoma, eosinophilic granuloma, chondroblastoma;    -   mesothelioma: e.g. pleural mesothelioma, peritoneal        mesothelioma;    -   cancers of the skin: e.g. basal cell carcinoma, squamous cell        carcinoma, Merkel's cell carcinoma, melanoma (including        cutaneous, superficial spreading, lentigo maligna, acral        lentiginous, nodular, intraocular melanoma), actinic keratosis,        eyelid cancer;    -   neoplasms of the central nervous system and brain: e.g.        astrocytoma (cerebral, cerebellar, diffuse, fibrillary,        anaplastic, pilocytic, protoplasmic, gemistocytary),        glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas,        ependymomas, ependymoblastomas, choroid plexus tumors,        medulloblastomas, meningiomas, schwannomas, hemangioblastomas,        hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas,        neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic),        spinal axis tumors;    -   lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL)        (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid        lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma        (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma        (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large        cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL),        cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma        (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell        lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma,        chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell        lymphocytic leukemia (TchlorineL) B-cell small lymphocytic        lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary        central nervous system lymphoma (PCNSL), immunoblastoma,        Hodgkin's disease (HD) (including nodular lymphocyte        predominance HD (NLPHD), nodular sclerosis HD (NSHD),        mixed-cellularity HD (MCHD), lymphocyte-rich classic HD,        lymphocyte-depleted HD (LDHD)), large granular lymphocyte        leukemia (LGL), chronic myelogenous leukemia (CML), acute        myelogenous/myeloid leukemia (AML), acute        lymphatic/lymphoblastic leukemia (ALL), acute promyelocytic        leukemia (APL), chronic lymphocytic/lymphatic leukemia (CLL),        prolymphocytic leukemia (PLL), hairy cell leukemia, chronic        myelogenous/myeloid leukemia (CML), myeloma, plasmacytoma,        multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes        (MDS), chronic myelomonocytic leukemia (CMML);    -   cancers of unknown primary site (CUP).

All cancers/tumors/carcinomas mentioned above which are characterized bytheir specific location/origin in the body are meant to include both theprimary tumors and the metastatic tumors derived therefrom.

All cancers/tumors/carcinomas mentioned above may be furtherdifferentiated by their histopathological classification:

Epithelial cancers, e.g. squamous cell carcinoma (SCC) (carcinoma insitu, superficially invasive, verrucous carcinoma, pseudosarcoma,anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC)(well-differentiated, mucinous, papillary, pleomorphic giant cell,ductal, small cell, signet-ring cell, spindle cell, clear cell, oatcell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinouscystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, smallcell carcinoma, neuroendocrine tumors (small cell carcinoma,paraganglioma, carcinoid); oncocytic carcinoma; Nonepithilial cancers,e.g. sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma,leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma,fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma,neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematologicalneoplasms, mixed and undifferentiated carcinomas.

In another aspect, the present invention relates to a compound ofFormula (I)—or a pharmaceutically acceptable salt thereof—for use in thetreatment and/or prevention of cancer, wherein the compound is to beadministered in combination with a cytostatic and/or cytotoxic activesubstance and/or in combination with radiotherapy and/or immunotherapy.

In another aspect, the present invention relates to a combination ofcompound of Formula (I)—or a pharmaceutically acceptable saltthereof—with a cytostatic and/or cytotoxic active substance and/or incombination with radiotherapy and/or immunotherapy for use in thetreatment and/or prevention of cancer.

In another aspect, the present invention relates to a method of treatingand/or preventing cancer, wherein said method comprises administering acompound of Formula (I)—or a pharmaceutically acceptable salt thereof—incombination with a cytostatic and/or cytotoxic active substance and/orin combination with radiotherapy and/or immunotherapy and/or targetedtherapy.

The compounds of the invention may be used on their own or incombination with one or several other pharmacologically activesubstances such as state-of-the-art or standard-of-care compounds, suchas e.g. cell proliferation inhibitors, anti-angiogenic substances,steroids or immune modulators/checkpont inhibitors, and the like.

Pharmacologically active substances which may be administered incombination with the compounds according to the invention, include,without being restricted thereto, hormones, hormone analogues andantihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide),aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole,exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelinacetate, luprolide), inhibitors of growth factors and/or of theircorresponding receptors (growth factors such as for example plateletderived growth factor (PDGF), fibroblast growth factor (FGF), vascularendothelial growth factor (VEGF), epidermal growth factor (EGF),insuline-like growth factors (IGF), human epidermal growth factor (HER,e.g. HER2, HER3, HER4) and hepatocyte growth factor (HGF) and/or theircorresponding receptors), inhibitors are for example (anti-)growthfactor antibodies, (anti-)growth factor receptor antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, afatinib,nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab andtrastuzumab); antimetabolites (e.g. antifolates such as methotrexate,raltitrexed, pyrimidine analogues such as 5fluorouracil (5fluorineU),ribonucleoside and deoxyribonucleoside analogues, capecitabine andgemcitabine, purine and adenosine analogues such as mercaptopurine,thioguanine, cladribine and pentostatin, cytarabine (ara C),fludarabine); antitumour antibiotics (e.g. anthracyclins such asdoxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride,myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicinand idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin,streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin,carboplatin); alkylation agents (e.g. estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas such as for example carmustin andlomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such asfor example vinblastine, vindesin, vinorelbin and vincristine; andtaxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g.tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARPinhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such asfor example etoposide and etopophos, teniposide, amsacrin, topotecan,irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Rafinhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Kαinhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKTinhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinaseinhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors),protein protein interaction inhibitors (e.g. IAP activator, Mel-1,MDM2/MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (e.g. KRASG12C inhibitors), signalling pathway inhibitors (e.g. SOS1 inhibitors),FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists,Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2/Bcl-xL inhibitors, ErbBreceptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors,rapamycin analogs (e.g. everolimus, temsirolimus, ridaforolimus,sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors,DNMT inhibitors, HDAC inhibitors, ANG1/2 inhibitors, CYP17 inhibitors,radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agentssuch as immune checkpont inhibitors (e.g. CTLA4, PD1, PD-L1, PD-L2,LAG3, and TIM3 binding molecules/immunoglobulins, such as e.g.ipilimumab, nivolumab, pembrolizumab), ADCC (antibody-dependentcell-mediated cytotoxicity) enhancers (e.g. anti-CD33 antibodies,anti-CD37 antibodies, anti-CD20 antibodies), T-cell engagers (e.g.bi-specific T-cell engagers (BiTEs®) like e.g. CD3×BCMA, CD3×CD33,CD3×CD19), PSMA×CD3), tumor vaccines and various chemotherapeutic agentssuch as amifostin, anagrelid, clodronat, filgrastin, interferon,interferon alpha, leucovorin, procarbazine, levamisole, mesna, mitotane,pamidronate and porfimer.

In another aspect the invention relates to a pharmaceutical compositioncomprising at least one compound of Formula (I)—or a pharmaceuticallyacceptable salt thereof—and optionally at least one pharmaceuticallyacceptable carrier.

In another aspect the invention relates to a pharmaceutical compositioncomprising a compound of Formula (I)—or a pharmaceutically acceptablesalt thereof—and at least one other cytostatic and/or cytotoxic activesubstance.

Suitable preparations for administering the compounds of the inventionwill be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions—particularly solutions for injection (s.c., i.v., i.m.) andinfusion (injectables)—elixirs, syrups, sachets, emulsions, inhalativesor dispersible powders.

Suitable tablets may be obtained, for example, by mixing one or morecompounds of Formula (I) with known excipients, for example inertdiluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants.

The dosage range of the compounds of Formula (I) applicable per day isusually from 1 mg to 2000 mg, preferably from 10 to 1000 mg.

The dosage for intravenous use is from 1 mg to 1000 mg with differentinfusion rates, preferably between 5 mg and 500 mg with differentinfusion rates.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, age, the route ofadministration, severity of the disease, the individual response to thedrug, the nature of its formulation and the time or interval over whichthe drug is administered (continuous or intermittent treatment with oneor multiple doses per day). Thus, in some cases it may be sufficient touse less than the minimum dose given above, whereas in other cases theupper limit may have to be exceeded. When administering large amounts itmay be advisable to divide them up into a number of smaller doses spreadover the day.

General Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skilled in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆ alkylmeans an alkyl group or radical having 1 to 6 carbon atoms.

In groups like OH, NH₂, S(O), S(O)₂, CN (cyano), COOH, CF₃ or the like,the skilled artisan can see the radical attachment point(s) to themolecule from the free valences of the group itself.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk may be used in subformulas to indicate thebond which is connected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

The term “halogen” denotes fluorine, chlorine, bromine and/or iodineatoms.

The term “heterocyclyl” or “heterocycle” means a saturated orunsaturated mono- or polycyclic-ring systems including aromatic ringsystem containing one or more heteroatoms selected from N, O orS(O)_(r), wherein r=0, 1 or 2, consisting of 3 to 14 ring atoms whereinnone of the heteroatoms is part of the aromatic ring. The term“heterocyclyl” or “heterocycle” is intended to include all the possibleisomeric forms.

Thus, the term “heterocyclyl” or “heterocycle” includes the followingexemplary structures which are not depicted as radicals as each form areoptionally attached through a covalent bond to any atom so long asappropriate valences are maintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

Unless specifically indicated, throughout the specification and appendedclaims, a given chemical formula or name shall encompass tautomers andall stereo, optical and geometrical isomers (e.g. enantiomers,diastereomers, E/Z isomers, etc.) and racemates thereof, as well asmixtures in different proportions of the separate enantiomers, mixturesof diastereomers, or mixtures of any of the foregoing forms where suchisomers and enantiomers exist, and solvates thereof, such as forinstance hydrates of the free compound.

In general, substantially pure stereoisomers can be obtained accordingto synthetic principles known to a person skilled in the field, e.g. byseparation of corresponding mixtures, by using stereochemically purestarting materials and/or by stereoselective synthesis. It is known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, e.g. starting from optically activestarting materials and/or by using chiral reagents.

Enantiomerically pure compounds of this invention or intermediates maybe prepared via asymmetric synthesis, for example by preparation andsubsequent separation of appropriate diastereomeric compounds orintermediates which can be separated by known methods (e.g. bychromatographic separation or crystallization) and/or by using chiralreagents, such as chiral starting materials, chiral catalysts or chiralauxiliaries.

Further, it is known to the person skilled in the art how to prepareenantiomerically pure compounds from the corresponding racemic mixtures,such as by chromatographic separation of the corresponding racemicmixtures on chiral stationary phases, or by resolution of a racemicmixture using an appropriate resolving agent, e.g. by means ofdiastereomeric salt formation of the racemic compound with opticallyactive acids or bases, subsequent resolution of the salts and release ofthe desired compound from the salt, or by derivatization of thecorresponding racemic compounds with optically active chiral auxiliaryreagents, subsequent diastereomer separation and removal of the chiralauxiliary group, or by kinetic resolution of a racemate (e.g. byenzymatic resolution); by enantioselective crystallization from aconglomerate of enantiomorphous crystals under suitable conditions, orby (fractional) crystallization from a suitable solvent in the presenceof an optically active chiral auxiliary.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings without excessive toxicity, irritation,allergic response, or other problem or complication, and commensuratewith a reasonable benefit/risk ratio.

As used herein “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

For example, such salts include salts from benzenesulfonic acid, benzoicacid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid,hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonicacid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonicacid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid andtartaric acid.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base form of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts), also comprise a part of the invention.

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different parts of the molecule,it is pointed out that the various uses are to be regarded as totallyindependent of one another.

The term “therapeutically effective amount” as used herein refers to aquantity of substance that is capable of obviating symptoms of illnessor of preventing or alleviating these symptoms, or which prolong thesurvival of a treated patient.

The term “prodrug” as used herein refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can be readily prepared fromthe parent compounds using methods known in the art, such as thosedescribed in A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991,particularly Chapter 5: “Design and Applications of Prodrugs”; Design ofProdrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical andOcular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods inEnzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985,particularly pp. 309-396; Burger's Medicinal Chemistry and DrugDiscovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987,each of which is incorporated herein by reference in their entireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans without undue toxicity, irritation, allergic response, and thelike, commensurate with a reasonable benefit/risk ratio, and effectivefor their intended use, as well as the zwitter ionic forms, wherepossible.

The term “compound selective over EGFR wild type” as used herein refersto a compound exhibiting higher efficacy on HER2 compared to EGFR, wherethe efficacy of the compound can be determined in a biological assaysuch as a BA/F3 proliferation assay, or a tumor cell line proliferationassay as described below.

The term “sparing EGFR wild type” or “EGFR wild type sparing activity”as used herein refers to the low EGFR wild type efficacy of a compound,which can be determined in a biological assay such as a BA/F3proliferation assay, or a tumor cell line proliferation assay asdescribed below.

The term “cancer with HER2 amplification” as used herein refers to acancer where the cancer cells exhibit more than 2 gene copies of ERBB2.

The term “cancer with HER2 overexpression” as used herein refers to acancer, where the cells of the cancer express HER2 at levels detectableby immunohistochemistry and/or methods assaying ERBB2 messenger RNA.

The term “mutant HER2” or “HER2 carrying exon 20 mutation” as usedherein refers to the mutant HER2 protein and concordant mutant DNAvariant, whereas “HER2 exon 20 mutant” as used herein refers to the HER2exon 20 mutant protein and concordant mutant DNA variant.

The term “HER2-mutant cancer” or “cancer with HER2 mutations” refers toa cancer where the cancer or tumor cells harbour HER2 mutation(s)including but not limited to the mutations listed in Table 1 and Table2.

The term “cancer with HER2 exon 20 mutation” or “HER2 exon 20 mutantcancer” as used herein refers to a cancer where the cancer or tumorcells harbour at least one HER2 exon 20 mutation including but notlimited to the mutations listed in Table 1.

ERBB2 (HER2) exon 20 encodes for a part of the kinase domain and rangesfrom amino acids 769 to 835. Every mutation, insertion, duplication ordeletion within this region is defined as an exon 20 mutation includingmutations listed in Table 1. In addition oncogenic HER2 mutations existoutside of exon 20 including mutations listed in Table 2.

TABLE 1 ERBB2 (HER2) exon 20 mutations (“p.” is referring to the HER2protein) p.A772_G773insMMAY p.Y772_A775_dup (YVMA) p.A775_G776insYVMAp.Y772insYVMA p.M774delinsWLV p.A775_G776insSVMA p.A775_G776insVVMAp.A775_G776insYVMS p.A775_G776insC p.A776_delinsVC p.A776_delinsLCp.A776_delinsVV p.A776_delinsAVGC p.A776_delinsIC p.A776_V777delinsCVCp.V777_insE p.G778_P780dup (GSP)

TABLE 2 Alternative HER2 mutations (“p.” is referring to the HER2protein) p.S310F p.R678Q p.L755S p.S310Y p.V842I p.D769Y p.D769H p.R103Qp.G1056S p.1767M p.L869R p.L869R p.T733I p.T862A p.V697L p.R929W p.D277Hp.D277Y p.G660D

List of Abbreviations

APCI atmospheric pressure chemical ionization aq. aqueous Boctert-butyloxycarbonyl DMF N,N-dimethylformamide DMSO dimethylsulfoxideES electrospray ESI electrospray ionization FBS Fetal bovine serum hhour(s) HPLC high performance liquid chromatography LC liquidchromatography min minutes MS mass spectrometry MSD mass selectivedetector RP reversed phase sat. saturated tert tertiary THFtetrahydrofuran TLC thin layer chromatography tRet. retention time UPLCUltra performance liquid chromatography UV ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed examples, which illustrate the principles ofthe invention by way of example without restricting its scope:

Preparation of the Compounds According to the Invention General

The compounds according to the present invention and their intermediatesmay be obtained using methods of synthesis which are known to the oneskilled in the art and described in the literature of organic synthesis.Preferably, the compounds are obtained in analogous fashion to themethods of preparation explained more fully hereinafter, in particularas described in the experimental section. In some cases, the order incarrying out the reaction steps may be varied. Variants of the reactionmethods that are known to the one skilled in the art, but not describedin detail here, may also be used.

The general processes for preparing the compounds according to theinvention will become apparent to the one skilled in the art studyingthe following schemes. Starting materials may be prepared by methodsthat are described in the literature or herein, or may be prepared in ananalogous or similar manner. Any functional groups in the startingmaterials or intermediates may be protected using conventionalprotecting groups. These protecting groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar tothe one skilled in the art.

General Reaction Schemes and Summary of the Synthesis Route

Compounds C according to the invention can be synthesized starting fromcommercially available para-flouronitrobenzenes (A) and alcohols, whichare reacted in a substitution reaction and subsequent reduction of thenitro-group to yield the corresponding amines C (see e.g. Ishikawa etal., J. Med. Chem. 2011, 54 (23), 8030-8050; McDaniel et al., J. Med.

Chem. 2017, 60 (20), 8369-8384).

Compounds F according to the invention can be synthesized according toGeneral Route 1 from compound D (see e.g. Wang et al. Bioorg. Med. Chem.Lett. 2016, 26 (11), 2589-2593, Wan et al., Org. Lett. 2006, 8, 11,2425-2428). Alternatively, compounds F according to the invention can besynthesized according to General Route 2 from compound G, which issubstituted with the relevant aniline (see e.g. Wang et al., Bioorg.Med. Chem. Lett. 2016, 26 (11), 2589-2593, Wan et al., Org. Lett. 2006,8, 11, 2425-2428). The alkylsulfide H is oxidized to the sulfoxide J orsulfone and substituted with the substituted or unsubstituted amines(see e.g. Del Bello et al., Bioorg. Med. Chem. 2015, 23 (17),5725-5733).

Compounds of Formula (I) according to the invention can be synthesizedfrom compounds F by deprotecting the Boc-protected substituted orunsubstituted amine and subsequent reaction with acryloyl chloride oracryloyl anhydride (see e.g. Zhang et al., Eur. J. Med.

Chem. 2019, 178, 417-432).

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

The compounds according to the invention are named in accordance withCAS rules using the software AutoNom (Beilstein) or MarvinSketch(ChemAxon, product version 17.24.3). If a compound is to be representedboth by a structural formula and by its nomenclature, in the event of aconflict the structural formula is decisive.

The example compounds of Formula (I), I-01 to I-19, and intermediatesare prepared by the methods of synthesis described hereinafter in whichthe substituents of the general formulae have the meanings givenhereinbefore. These methods are intended as an illustration of theinvention without restricting its subject matter and the scope of thecompounds claimed to these examples. Where the preparation of startingcompounds is not described, they are commercially obtainable or theirsynthesis is described in the prior art or they may be preparedanalogously to known prior art compounds or methods described herein,i.e. it is within the skills of an organic chemist to synthesize thesecompounds. Substances described in the literature can be preparedaccording to the published methods of synthesis.

Chromatography

Thin layer chromatography is carried out on ready-made silica gel 60 TLCplates on glass (with fluorescence indicator F-254) made by Merck.

Preparative high pressure chromatography (RP HPLC) of the examplecompounds is carried out on Agilent or Gilson systems with columns madeby Waters (names: SunFire™ Prep C18, OBD™ 10 μm, 50×150 mm or SunFire™Prep C18 OBD™ 5 μm, 30×50 mm or XBridge™ Prep C18, OBD™ 10 μm, 50×150 mmor XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm or XBridge™ Prep C18, OBD™ 5μm, 30×50 mm) and YMC (name: Actus-Triart Prep C18, 5 μm, 30×50 mm).

Different gradients of H₂O/acetonitrile are used to elute the compounds.For Agilent systems 5% acidic modifier (20 mL HCOOH to 1 LH₂O/acetonitrile (1/1)) is added to the water (acidic conditions). ForGilson systems 0.1% HCOOH is added to the water.

For the chromatography under basic conditions for Agilent systemsH₂O/acetonitrile gradients are used, 5% basic modifier is added to theaqueous eluent (50 g NH₄HCO₃+50 mL NH₃ (25% in H₂O)+H₂O for 1 L aqueouseluent). For Gilson systems the aqueous eluent consists of 5 mL NH₄HCO₃solution (158 g in 1 L H₂O) and 2 mL NH₃ (28% in H₂O), replenished to 1L with H₂O.

HPLC-MS columns used were from Waters (XBridge™ C18, 2.5 μm, 2.1×20 mmor XBridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLC BEH C18, 1.7 μm,2.1×50 mm), YMC (Triart C18, 3.0 μm, 2.0×30 mm) and Phenomenex (LunaC18, 5.0 μm, 2.0×30 mm).

HPLC-Mass Spectroscopy/UV-Spectrometry

The retention times/MS-ESI⁺ for characterizing the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector). Compounds thatelute at the injection peak are given the retention time t_(Ret).=0.00.

Method 1 HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (MM-ES +APCI + 3000 V, Quadrupol, G6130) MSD signal Scan pos 150-750 settingscolumn Waters; Part. No. 186003020; XBridge BEH C18, 3.5 μm, 30 × 2.1 mmcolumn or Waters; Part. No. 186006028; XBridge BEH C18 XP, 2.5 μm, 30 ×2.1 mm column eluent 5 mM NH₄HCO₃/18 mM NH₃ (pH = 9.2) B: acetonitrile(HPLC grade) detection UV 254 nm (bandwidth 8, reference off) signalspectrum range: 190-400 nm; step: 2 nm peak width >0.0031 min (0.063 s)(80 Hz) injection 0.5 μL standard injection flow 1.4 mL/min column  45°C. temperature gradient 0.0-1.0 min 15% → 95% B 1.0-1.3 min 95% B Stoptime: 1.3 min Method 2 HPLC Agilent 1100/1200 system MS 1200 SeriesLC/MSD (API-ES +/− 3000 V, Quadrupol, G6140) MSD signal Scan pos150-750, Scan neg 150-750 settings column YMC; Part. No. TA12S03-0302WT;Triart C18, 3 μm, 12 nm; 30 × 2.0 mm column eluent A: H₂O + 0.11% formicacid B: acetonitrile + 0.1% formic acid (HPLC grade) detection UV 254 nm(bandwidth 10, reference off) signal spectrum range: 190-400 nm; step: 4nm peak width >0.005 min (0.1 s) injection 0.5 μL standard injectionflow 1.4 mL/min column  45° C. temperature gradient 0.0-1.0 min 15% →100% B 1.0-1.1 min 100% B Stop time: 1.23 min Method 3 HPLC Agilent1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/− 4000 V,Quadrupol, G6130) MSD signal Scan pos 150-800, Scan neg 150-800 settingscolumn Waters; Part. No. 186003020; XBridge BEH C18, 3.5 μm, 30 × 2.1 mmcolumn or Waters; Part. No. 186006028; XBridge BEH C18 XP, 2.5 μm, 30 ×2.1 mm column eluent 5 mM NH₄HCO₃/18 mM NH₃ (pH = 9.2) B: acetonitrile(HPLC grade) detection UV 254 nm (bandwidth 8, reference off) signalspectrum range: 190-400 nm; step: 4 nm peak width >0.0031 min (0.063 s)injection 0.5 μL standard injection flow 1.4 mL/min column  45° C.temperature gradient 0.0-1.0 min 15% → 95% B 1.0-1.3 min 95% B Stoptime: 1.3 min Method 4 HPLC Agilent 1100/1200 system MS 1200 SeriesLC/MSD (API-ES +/− 3000 V, Quadrupol, G6140) MSD signal Scan pos 150-750settings column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm;30 × 2.0 mm column eluant A: H₂O + 0.11% formic acid B: MeCN + 0.1%formic acid (HPLC grade) detection UV 254 nm (bandwidth 10, referenceoff) signal spectrum range: 190-400 nm; step: 4 nm peak width >0.005 min(0.1 s) injection 0.5 μL standard injection flow 1.4 mL/min column  45°C. temperature gradient 0.0-1.0 min 15% → 100% B 1.0-1.1 min 100% B Stoptime: 1.23 min Method 5 HPLC Agilent 1260 system MS 1200 Series LC/MSD(API-ES +/− 3000 V, Quadrupol, G6140) MSD signal Scan pos/neg 120-900m/z settings column Waters, Xbridge C18, 2.5 μm, 2.1 × 20 mm columneluent A: 20 mM NH₄HCO₃/NH₃ pH 9 B: acetonitrile HPLC grade detection315 nm (bandwidth 170 nm, reference off) signal spectrum range: 230-400nm peak width <0.01 min injection   5 μL standard injection column   60°C. temperature flow 1.00 mL/min gradient 0.00-1.50 min 10% → 95% B1.50-2.00 min 95% B 2.00-2.10 min 95% → 10% B Method 6 HPLC Agilent1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/− 3000 V,Quadrupol, G6130B) MSD signal Scan pos/neg 150-750 settings columnWaters, Part. No. 186003389, XBridge BEH C18, 2.5 μm, 2.1 × 30 mm)column eluent A: 5 mM NH₄HCO₃/18 mM NH₃ (pH = 9.2) B: acetonitrile (HPLCgrade) detection UV 254 nm, 230 nm, 214 nm (bandwidth 8, reference off)signal spectrum range: 190-400 nm; slit: 4 nm peak width >0.0031 min(0.063 s response time, 80 Hz) injection 0.5 μL standard injection flow1.4 mL/min column  45° C. temperature gradient 0.0-1.0 min 15% → 95% B1.0-1.1 min 95% B Stop time: 1.3 min Method 7 HPLC Agilent 1100/1200Series MS Agilent LC/MSD SL column Waters X-Bridge BEH C18, 2.5 μm, 2.1× 30 mm XP eluent A: 5 mM NH₄HCO₃/19 mM NH₃ in H₂O; B: acetonitrile(HPLC grade) detection MS: positive and negative mode signal mass range 100-1200 m/z flow 1.40 mL/min column   45° C. temperature gradient0.00-1.00 min: 5% B → 100% B 1.00-1.37 min: 100% B 1.37-1.40 min: 100% B→ 5% B Method 8 HPLC Agilent RRLC MS Agilent Technologies -6130Quadrupole LC/MS MSD signal Scan positive 70-1200, Scan negative 70-1200settings column X-Bridge C18, 4.6 × 75 mm, 3.5 μm eluent A: 10 mMNH₄HCO₃ in H₂O, B: acetonitrile (HPLC grade) detection UV 215/254 nm(Bandwidth 4, Reference off) signal spectrum Range: 200-400 nm; step: 2nm peak width >0.1 min (2.0 s response time) (2.5 Hz) injection 4.0 μLinjection with needle wash flow rate 2.0 mL/min column 35° C.temperature gradient 0.0-0.2 min: 10% B 0.2-2.5 min: 10% → 75% B 2.5-3.0min: 75% → 100% B 3.0-4.8 min: 100% B 4.8-5.0 min: 100% → 10% B Method 9HPLC Waters Acquity-UPLC-SQ Detector-2 column AQUITY UPLC BEH C18 1.7μm, 2.1 × 50 mm eluent A: 0.07% formic acid in acetonitrile, B: 0.07%formic acid in water flow rate 0.6 mL/min column  35° C. temperaturegradient 0.0-0.3 min: 97% B 0.3-2.2 min: 97% → 2% B 2.2-4.5 min: 2% B4.5-4.51 min: 2% → 97% B Method 10 HPLC Thermo Scientific, DionexUltimate-3000 MS Thermo Scientific LCQ FLEET (Ion Trap) MSD signal ESIMODE, Scan Pos & Neg 100-1500 settings column X-Bridge C18 2.5 μm, 4.6 ×50 mm eluent A: 10 mM NH₄HCO₃ in H₂O, B: acetonitrile (HPLC grade)detection Diode Array signal spectrum Range: 200-400 nm; DetectionSignal: 215 & 254 nm flow rate 1.0 mL/min column  35° C. temperaturegradient  0.0-0.80 min: 5% B 0.80-4.0 min: 5% → 75% B  4.0-5.0 min: 75%→ 98% B  5.0-6.80 min: 98% B 6.80-8.0 min: 98% → 5% B Method 11 HPLC -MSWaters Acquity-Binary Solvent Manager-UPLC-SQ Detector-2 MSD signal Scanpos & Neg 100-1500 settings column AQUITY UPLC BEH C18 1.7 μm, 2.1 × 50mm eluent A: 0.07% formic acid in acetonitrile, B: 0.07% formic acid inwater detection Diode Array signal spectrum Range: 200-400 nm;resolution: 1.2 nm injection 0.5 μL standard injection flow rate 0.6mL/min column  35° C. temperature gradient  0.0-0.40 min: 97% B0.40-2.50 min: 97% → 2% B 2.50-3.40 min: 2% B 3.40-3.50 min: 2% → 97% B3.50-4.0 min: 97% B

Synthesis of Compounds C

Synthesis of B-01

1-Methyl-1H-benzo[d]imidazol-5-ol (500 mg, 3.38 mmol),1-fluoro-2-methyl-4-nitrobenzene (681 mg, 4.39 mmol) and potassiumcarbonate (1.16 g, 8.44 mmol) in DMF (5 mL) are stirred at 80° C. for 6h. The reaction mixture is concentrated. The crude product is purifiedby column chromatography (SiO₂, cyclohexane/ethyl acetate gradient).Compounds B-02-B-09 (Table 1) are synthesized analogously to theprocedure shown above.

TABLE 1 Example t_(Ret) Number Structure [min] [M + H]⁺ Method B-01

1.25 284 5 B-02

0.41 294 2 B-03

1.09 300 5 B-04

2.66 304 8 B-05

0.50 308 3 B-06

0.50 271 3 B-07

2.35 281 9 B-08

1.15 270 5 B-09

1.13 285 5

Synthesis of C-01 and C-05 Method 1—Synthesis of C-01

B-01 (950 mg, 3.35 mmol) and 10% Pd/C (100 mg) in ethanol (10 mL)/THF(10 mL) are stirred under a hydrogen atmosphere (3 bar) for 24 h at atemperature of 18-25° C. The reaction mixture is filtered andconcentrated in vacuo.

Compounds C-03 and C-06-C-08 (Table 2) are synthesized analogously tothe procedure shown above.

Method 2—Synthesis of C-05

B-05 (250 mg, 0.81 mmol) and iron (226 mg, 55.8 mmol) are suspended inethanol and sat. aq. NH₄Cl solution. The resulting reaction mixture isstirred at 80° C. for 3 hours and subsequently at a temperature of18-25C for 16 hours. The reaction mixture is filtered over a pad ofcelite and the filtrate is concentrated in vacuo. The resulting residueis used in the next synthetic step without further purification.

Compounds C-02, C-04, and C-09 (Table 2) are synthesized analogously tothe procedure shown above.

TABLE 2 Example t_(Ret) Number Structure [min] [M + H]⁺ Method C-01

0.98 254 5 C-02

0.37 264 3 C-03

0.84 270 5 C-04

0.43 274 3 C-05

0.43 279 3 C-06

0.86 241 5 C-07

1.90 251 9 C-08

0.93 240 5 C-09

0.85 255 5

Synthesis of Compounds F Synthesis of Compounds F According to GeneralRoute 1 (Scheme 2)

Synthesis of E-01

6-Methanesulfinyl[1,3]diazino[5,4-d]pyrimidin-4-ol(6-Methanesulfinylpyrimido[5,4-d]pyrimidin-4-ol, D, 211 mg, 1.00 mmol,prepared according to WO9732880) andtert-butyl-N-(piperidin-4-yl)carbamate (246 mg, 1.20 mmol) in dioxane (4mL) are stirred under reflux for 16 h. The reaction mixture isconcentrated under reduced pressure, and the crude product is purifiedby column chromatography (SiO₂, dichloromethane/methanol gradient).Compound E-02 (Table 3) is synthesized analogously to the procedureshown above.

TABLE 3 Example t_(Ret) Number Structure [min] [M + H]⁺ Method E-01

0.93 347 5 E-02

0.43 361 3

Synthesis of F-03

E-01 (200 mg, 0.55 mmol),benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(441 mg, 0.83 mmol) and 1,8-diazabicyclo[5.4.0]endec-7-ene (126 mg, 0.83mmol) in dry THF (4 mL) are stirred at a temperature of 18-25° C. for 30minutes. C-03 (205 mg, 0.66 mmol) in dry THF (1 mL) is added, and themixture is stirred at 70° C. for 16 h. The mixture is concentrated invacuo, and the crude product is purified by preparative reversed phaseHPLC.

Compounds F-04, F-06, and F-12 (Table 6) are synthesized analogously tothe procedure shown above.

Synthesis of Compounds F According to General Route 2 (Scheme 3)

Synthesis of H-01

8-Chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine (500 mg, 1.97 mmol) andC-01 (492 mg, 1.97 mmol) in isopropanol (10 mL) are stirred at 50° C.for 3 h. The precipitate is collected by filtration, and the crudeproduct is purified by column chromatography (SiO₂,dichloromethane/methanol gradient) to give the product H-01.

Compounds H-02-H-06 (Table 4) are synthesized analogously to theprocedure shown above. The product may also be isolated by partitioningthe reaction mixture between organic solvent and aqueous layer, reducingthe organic layer in vacuo, and column purification of the crudeproduct.

TABLE 4 Example t_(Ret) Number Structure [min] [M + H]⁺ Method H-01

0.45 430 3 H-02

2.47 441 9 H-03

4.39 450 10 H-04

0.59 417 3 H-05

1.82 427 11 H-06

2.33 431 9

Synthesis of J-01

To H-01 (860 mg, 1.80 mmol) in dichloromethane (30 mL),m-chloroperbenzoic acid (77%, 444 mg, 1.98 mmol) is added at 5° C., andthe reaction mixture is stirred at a temperature of 18-25° C. for 2 h.Sat. aq. NaHCO₃ solution (200 mL) is added, and the aqueous layer isextracted with dichloromethane several times. The combined organic layeris washed with water, dried (Mg₂SO₄), filtered, and concentrated invacuo. The crude product J-01 is used in the next step without furtherpurification.

Compounds J-02-J-06 (Table 5) are synthesized analogously to theprocedure shown above.

TABLE 5 Exam- ple t_(Ret) Number Structure [min] [M + H]⁺ Method J-01

0.46 446 3 J-02

1.35 456 11 J-03

2.29 466 8 J-04

0.94 433 5 J-05

4.78 443 9 J-06

1.41 447 11

Synthesis of F-01

J-01 (5.42 g, 9.74 mmol), tert-butyl-N-(piperidin-4-yl)carbamate (2.39g, 11.7 mmol) and N-ethyl-diisopropylamine (2.51 g, 19.4 mmol) in DMF(50 mL) are stirred at 60° C. for 16 h. The reaction mixtureconcentrated in vacuo, and the crude product is used without furtherpurification for the next step.

Compounds F-02, F-05, F-07-F-11, and F-13-F-19 (Table 6) are synthesizedanalogously to the procedure shown above.

TABLE 6 Example t_(Ret) Number Structure [min] [M + H]⁺ Method F-01

1.43 582 5 F-02

0.70 592 1 F-03

1.29 598 5 F-04

1.43 612 5 F-05

0.78 602 6 F-06

0.75 607 6 F-07

0.65 554 3 F-08

0.73 574 3 F-09

1.27 541 5 F-10

0.65 551 6 F-11

0.69 569 3 F-12

1.39 568 5 F-13

0.89 555 7 F-14

0.75 582 6 F-15

0.60 592 4 F-16

0.69 569 1 F-17

0.65 555 1 F-18

0.65 555 1 F-19

0.61 541 6

Synthesis of I-01-I-19

Synthesis of K-01

To F-01 (5.66 g, 9.73 mmol) in dry dichloromethane (100 mL) and methanol(30 mL), HCl (4 N in dioxane, 22 mL) is added. The reaction mixture isstirred at 45° C. for 4 h, and then concentrated in vacuo. The crudeproduct is purified by column chromatography (SiO₂,dichloromethane/methanol gradient).

Compounds K-02-K-19 (Table 7) are synthesized analogously to theprocedure shown above.

TABLE 7 Example t_(Ret) Number Structure [min] [M + H]⁺ Method K-01

1.14 482 5 K-02

1.08 492 5 K-03

1.01 498 5 K-04

0.49 512 3 K-05

0.56 502 6 K-06

1.14 507 5 K-07

0.45 454 3 K-08

0.50 474 3 K-09

0.97 441 5 K-10

0.43 451 6 K-11

0.44 469 3 K-12

0.49 468 3 K-13

0.95 455 5 K-14

0.50 482 3 K-15

0.99 492 5 K-16

1.14 469 5 K-17

1.00 455 5 K-18

1.00 455 5 K-19

0.30 441 2

Synthesis of I-01

To K-01 (168 mg, 0.15 mmol) in dry dichloromethane (2 mL) acryloylchloride (13 μL, 0.16 mmol) and diisopropylethylamine (149 μL, 0.88mmol) are added and stirred stirred at a temperature of 18-25° C. for 1h. The reaction mixture is concentrated in vacuo, and the crude productis purified by preparative RP-HPLC-MS.

Compounds I-02-I-19 (Table 8) are synthesized analogously to theprocedure shown above.

TABLE 8 t_(Ret) Name Structure [min] [M + H]⁺ Method I-01

1.18 536 5 I-02

1.13 546 5 I-03

1.09 552 5 I-04

1.20 566 5 I-05

1.21 556 5 I-06

1.19 561 5 I-07

1.11 508 5 I-08

1.13 528 5 I-09

1.04 495 5 I-10

1.02 505 5 I-11

1.12 523 5 I-12

1.15 522 5 I-13

1.02 509 5 I-14

1.16 536 5 I-15

1.10 546 5 I-16

1.12 523 5 I-17

1.09 509 5 I-18

1.09 509 5 I-19

1.03 495 5

Biological Assays Ba/F3 Cell Model Generation and Proliferation Assays

Ba/F3 cells were ordered from DSMZ (ACC300) and are grown in RPMI-1640(ATCC 30-2001)+10% FBS+10 ng/ml IL-3 at 37° C. in 5% CO₂ atmosphere.Plasmids containing HER2 mutants and EGFR WT were obtained fromGeneScript. To generate EGFR/HER2-dependent Ba/F3 models, Ba/F3 cellsare transduced with retroviruses containing vectors that harbor EGFR WT,HER2 WT or HER2 mutants (YVMA). Platinum-E cells (Cell Biolabs) are usedfor retrovirus packaging. Retrovirus is added to Ba/F3 cells. To ensureinfection, 4 μg/mL polybrene is added and cells are spin-infected.Infection efficiency is confirmed by measuring GFP-positive cells usinga cell analyzer. Cells with an infection efficiency of 10% to 20% arefurther cultivated and puromycin selection with 1 μg/mL is initiated. Asa control, parental Ba/F3 cells are used to assess the selection status.Selection is considered successful when parental Ba/F3 cells culturesdie. To evaluate the transforming potential of HER2 mutations, thegrowth medium is no longer supplemented with IL-3. Ba/F3 cells harboringthe empty vector are used as a control. A switch from IL-3 to EGF isperformed for Ba/F3 cells expressing EGFR WT known for its dependency onEGF ligand. Approximately ten days before conducting the experiments,puromycin is left out. For proliferation assays (data in tables 10 and12), Ba/F3 cells are seeded into 96-well plates at 5×10³ cells/100 μL ingrowth media. Compounds are added by using a HP D3000 Digital Dispenser.All treatments are performed in technical triplicates. Treated cells areincubated for 72 h at 37° C. with 5% CO₂. A CellTiter-Glo® LuminescentCell Viability Assay (Promega) is performed and chemoluminescence ismeasured by using the multilabel Plate Reader VICTOR X4. The raw dataare imported into and analyzed with the Boehringer Ingelheim proprietarysoftware MegaLab (curve fitting based on the program PRISM, GraphPadInc.).

pEGFR Assay

This assay quantifies the phosphorylation of EGFR at Tyr1068 and is usedto measure the inhibitory effect of compounds on the transgenic EGFRwild type (WT) protein expressed in HEK cells.

Human HEK cells (ATCC CRL-1573) are grown in Minimum essential MediumEagle, MEM Eagle EBSS, without L-Glutamine, with non essential aminoacids and sodium pyruvate (EMEM Lonza BE12-662F)+5 ml GlutaMax (Gibco35050-038; L-alanyl-L-glutamine)+5 ml Sodium Pyruvat (Gibco; 100 mM)+10%FBS at 37° C. in 5% CO₂ atmosphere and transduced with a retroviralvector encoding EGFR WT. Transduced cells are selected using puromycin.p-EGFR Tyr1068 is determined using the AlphaScreen Surefire pEGFReceptor (Tyr1068) Assay (PerkinElmer, TGRERS). For the assay, HEK EGFRWT cells are seeded in MEM medium with 10% FBS. 60 nL compound dilutionswere added to each well of Greiner TC 384 plates using the Echoplatform. Subsequently, 60.000 cells/well in 60 μL are added. Cells areincubated with compound for 4 h at 37° C. Following centrifugation andremoval of the medium supernatant, 20 μL of 1.6-fold lysis buffer fromTGR/Perkin Elmer kit with protease inhibitors is added. The mixture isincubated at a temperature of 20-25° C. with shaking (700 rpm) for 20min. After centrifugation, 4 μL of the lysate are transferred toProxiplates. 5 μL of Acceptor Mix (Activation Buffer diluted 1:25 incombined Reaction Buffer 1 and Reaction Buffer 2 (TGRERS Assay Kit,PerkinElmer) plus 1:50 of Protein A Acceptor Beads 6760137, PerkinElmer) are added to each well. Plates are shaken for 1 min (1400 rpm)and incubated for 2 h at a temperature of (20-25° C.) in the dark. 3 μLof donor mix (AlphaScreen Streptavidin-coated Donor Beads (6760002,PerkinElmer) 1:50 diluted in Dilution Buffer (TGRERS Assay Kit,PerkinElmer)) are added to each well. Plates are shaken for 1 min (1400rpm) and incubated for 2 h at a temperature of (20-25° C.) in the dark.Plates are subsequently analyzed using an Envision reader platform.Results are computed in the following way: The ratio of the value of thetest compound and the value of the negative control (DMSO) iscalculated. IC₅₀ values are computed from these values in the MEGASTARIC₅₀ application using a 4 parametric logistic model.

This cellular phospho-EGFR (pEGFR) compound dose-response assayquantifies the phosphorylation of EGFR at Tyr1068 in HEK cellsexpressing EGFR WT. The results of the assay are provided as IC₅₀values. The higher the pEGFR IC₅₀ values for a given compound, thehigher the EGFR WT sparing activity.

pHER2 (ERBB2) YVMA Assay

This assay quantifies the phosphorylation of HER2 YVMA at Tyr1221/1222and is used to measure the inhibitory effect of compounds on thetransgenic HER2 YVMA protein expressed in HEK cells using a Doxycyclineinducible expression system.

Human HEK cells are grown in Minimum essential Medium Eagle, MEM EagleEBSS, without L-Glutamine, with non essential amino acids and sodiumpyruvate (EMEM Lonza BE12-662F)+5 mL GlutaMax (Gibco 35050-038;L-alanyl-L-glutamine)+5 mL Sodium Pyruvat (Gibco; 100 mM)+10% FBS at 37°C. in 5% CO2 atmosphere and transduced with a retroviral vector encodingHER2 YVMA. Transduced cells are selected using puromycin. p-ERBB2Tyr1221/1222 is determined using the AlphaScreen Surefire ErbB2(Tyr1221/1222) Assay (PerkinElmer, TGREB2S). For the assay, HEK HER2YVMA cells are seeded in MEM medium with 10% FBS. 4 hours prior tocompound addition, HER2 YVMA expression is induced using 1 μg/mLDoxycycline. 60 nL compound dilutions are added to each well of GreinerTC 384 plates using the Echo platform. Subsequently, 60.000 cells/wellin 60 μL are added. Cells are incubated with compound for 4 h at 37° C.Following centrifugation and removal of the medium supernatant, 20 μL of1.6-fold lysis buffer from TGR/Perkin Elmer kit with protease inhibitorsare added. The mixture is incubated at a temperature of 20-25° C. withshaking (700 rpm) for 20 min. After centrifugation, 4 μL of the lysateare transferred to Proxiplates. 5 μL of Acceptor Mix (Activation Bufferdiluted 1:25 in combined Reaction Buffer 1 and Reaction Buffer 2(TGREB2S Assay Kit, PerkinElmer) plus 1:50 of Protein A Acceptor Beads6760137, PerkinElmer) are added to each well. Plates are shaken for 1min (1400 rpm) and incubated for 2 h at a temperature of 20-25° C. inthe dark. 3 μL of donor mix (AlphaScreen Streptavidin-coated Donor Beads(6760002, PerkinElmer) 1:50 diluted in Dilution Buffer (TGRERS AssayKit, PerkinElmer)) are added to each well. Plates are shaken for 1 min(1400 rpm) and incubated for 2 h at a temperature of 20-25° C. in thedark. Plates are subsequently analyzed using an Envision readerplatform.

Results are computed in the following way: The ratio of the value of thetest compound and the value of the negative control (DMSO) iscalculated. IC₅₀ values are computed from these values in the MEGASTARIC₅₀ application using a 4 parametric logistic model.

This cellular phospho-HER2 YVMA (pHER2 YVMA) compound dose-responseassay quantifies the phosphorylation of HER2 YVMA at Tyr1221/1222 in HEKcells expressing HER2 YVMA. The results of the assay are provided asIC₅₀ values. The lower the reported pHER2 YVMA IC₅₀ values for a givencompound, the stronger the inhibitory effect of a compound on HER2 YVMAkinase activity.

HER2 YVMA Tumor Cell Line Model Generation and Proliferation Assays

HER2 WT-dependent NCI-H2170 cells were ordered from (ATCC, CRL-5928) andare grown in RPMI-1640 (Gibco #A10491) ATCC-Formulation+10% FCS at 37°C. in 5% CO2 atmosphere. Homology-directed genome engineering isemployed to insert a 12 nucleotide sequence encoding YVMA into Exon 20of the genomic HER2 locus in NCI-H2170 cells. This results in the changefrom HER2 WT to the HER2 YVMA variant representing HER2p.A775_G776insYVMA. The DNA template containing the HER2 exon 20 YVMAinsertion variant was obtained from GenScript. PCR followed by Sangersequencing is used to confirm the presence of the 12-nucleotideinsertion in HER2 Exon 20 resulting in the YVMA amino acid duplication.

For proliferation assays, NCI-H2170 (HER2 wild type), NCI-H2170 HER2YVMA and EGFR WT dependent A431 cells are used. NCI-H2170 HER2 YVMA orNCI-H2170 cells are seeded into 96-well plates at 750 cells/60 μL ingrowth media (RPMI ATCC+10% FCS, +Penicillin/Streptomycin). A431 cells(ATCC CRL-1555) (DMEM (Sigma #D6429)+5 mL Sodium Pyruvat Gibco11360-039) are plated at a density of 5000 cells per well (200 μL) in a96-well plate. Compounds are added by using a HP D3000 Digital Dispenserone day after plating the cells. All treatments are performed intechnical triplicates. Treated cells are incubated for 72 h at 37° C.with 5% CO2. CellTiter-Glo® Luminescent Cell Viability Assay (Promega)is performed and chemoluminescence is measured by using the multilabelPlate Reader VICTOR X4. The raw data are imported into and analyzed withthe Boehringer Ingelheim proprietary software MegaLab (curve fittingbased on the program PRISM, GraphPad Inc.).

TABLE 9 Biomarker Assay IC50 HEK IC50 HEK pHER2 pEGFR Name YVMA [nM][nM] I-01 13 579 I-02 34 628 I-03 20 916 I-04 26 495 I-05 10 315 I-06 44773 I-07 20 1170 I-08 58 336 I-09 26 715 I-10 24 217 I-11 22 521 I-12 16230 I-13 28 429 I-14 11 73 I-15 12 86 I-16 5 23 I-17 2 94 I-18 4 137I-19 8 41

TABLE 10 Proliferation Assays GI50 GI50 NCI H- NCI H- GI50 GI50 GI50GI50 2170 2170 A431 BAF3 BAF3 BAF3 HER2 HER2 EGFR HER2 HER2 EGF wt amp.YVMA wt amp. WT YVMA dep. Name [nM] [nM] [nM] [nM] [nM] [nM] I-01 633 >5000 1 16 1540 I-02 13 228 >5000 1 37 3010 I-03 11 139 >5000 238 >5000 I-04 12 99 >5000 3 32 >5000 I-05 8 55 >5000 1 21 1880 I-06 12215 >5000 1 31 >5000 I-07 17 73 >5000 3 42 1500 I-08 8 44 1500 2 36 2300I-09 9 75 >5000 1 29 2240 I-10 12 126 1460 3 35 1650 I-11 8 172 1250 228 >2000 I-12 8 71 >5000 2 18 1750 I-13 19 82 >5000 1 32 >2000 I-14 1037 >2000 2 17 756 I-15 13 44 948 2 18 425 I-16 4 19 660 1 10 375 I-17 939 >2000 2 14 1100 I-18 10 87 >2000 2 29 3270 I-19 8 34 752 11 206

TABLE 11 Biomarker Assay IC50 HEK IC50 pHER2 HEK YVMA pEGFR NameStructure [nM] [nM] Allitinib

3 1 Ibrutinib

26 21 Neratinib

1 4 Allitinib

3 1 Poziotinib

5 1 WO 2019/046775 Comp. 2

11 7 Allitinib

3 1 Tucatinib

4 1410 WO 2007/059257 Ex. 185

33 317

TABLE 12 Tumour Cell Proliferation Assay GI50 GI50 NCI H- NCI H- GI50GI50 GI50 GI50 2170 2170 A431 BAF3 BAF3 BAF3 HER2 HER2 EGFR HER2 HER2EGF wt amp. YVMA wt amp. WT YVMA dep. Name [nM] [nM] [nM] [nM] [nM] [nM]allitinib 36 203 403 17 31 ibrutinib 16 132 199 44 70 neratinib 3 37 551 5 14 poziotinib 1 5 1 1 2 1 WO 2019/ 22 34 16 3 14 13 046775 Comp. 2tucatinib 58 798 4220 10 338 2970 WO 2007/ 108 926 >5000 60 1190 059257Ex. 185

Example of Pharmaceutical Formulation

Ingredient Amount Active substance 100 mg lactose 140 mg corn starch 240mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg

The active substance is grounded and mixed together with lactose andsome of the corn starch. The mixture is sieved, then wet granulated withpolyvinylpyrrolidone solution. The granules, the remaining corn starchand the magnesium stearate are mixed together. The mixture is compressedto produce tablets of suitable shape and size.

1-14. (canceled)
 15. A pharmaceutical composition comprising one or morepharmaceutically acceptable excipients and a therapeutically effectiveamount of a compound according to Formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R¹ is halogen, CH₃, C≡CH, or OCH₃; R² is H or halogen; R³ is formula(i.1), formula (i.2), formula (i.3), or formula (i.4):

R⁴ is R^(4.a) or R^(4.b):

Q is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-memberedheterocyclyl contains one nitrogen heteroatom, and further wherein onecarbon atom of the 4- to 6-membered heterocyclyl is optionallysubstituted with CH₃; Z is a 4- to 6-membered heterocyclyl, wherein the4- to 6-membered heterocyclyl contains one nitrogen heteroatom, andfurther wherein one carbon atom of the 4- to 6-membered heterocyclyl isoptionally substituted with CH₃; and R⁵ is H or CH₃; with the provisothat at least one of R¹ and R² is not H.
 16. The pharmaceuticallyacceptable composition according to claim 1, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein R¹ is F.
 17. Thepharmaceutically acceptable composition according to claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ isCl.
 18. The pharmaceutically acceptable composition according to claim1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R¹ is CH₃.
 19. The compound according to claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ isC═CH.
 20. The compound according to claim 1, or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein R¹ is OCH₃.
 21. Thecompound according to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is H.
 22. The compound according toclaim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R² is Cl.
 23. The pharmaceutical composition according to claim1, or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R⁴ is R^(4.a) or R^(4.b);

wherein: R^(4.a) is R^(4.a.1)

wherein: R⁶ is H or CH₃; m is 1 or 2; and n is 1 or 2; and R^(4.b) isR^(4.b.1):

wherein: p is 1 or 2; and q is 1 or
 2. 24. The pharmaceuticalcomposition according to claim 1, or a stereoisomer thereof, wherein thecompound, or stereoisomer thereof, is selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of a compoundaccording to Formula (I)

or a pharmaceutically acceptable salt or stereoisomer thereof, andwherein: R¹ is halogen, CH₃, C≡CH, or OCH₃; R² is H or halogen; R³ isformula (i.1), formula (i.2), formula (i.3), or formula (i.4):

R⁴ is R^(4.a) or R^(4.b):

Q is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-memberedheterocyclyl contains one nitrogen heteroatom, and further wherein onecarbon atom of the 4- to 6-membered heterocyclyl is optionallysubstituted with CH₃; Z is a 4- to 6-membered heterocyclyl, wherein the4- to 6-membered heterocyclyl contains one nitrogen heteroatom, andfurther wherein one carbon atom of the 4- to 6-membered heterocyclyl isoptionally substituted with CH₃; and R⁵ is H or CH₃; with the provisothat at least one of R¹ and R² is not H; and a pharmaceutically activesubstance selected from the group consisting of a cytostatic activesubstance and a cytotoxic active substance.